Combinatorial therapy for treatment of osteoarthritis of the knee

ABSTRACT

Embodiments of the present invention generally relate to methods of knee rehabilitation. Embodiments generally include the use of viscosupplementation delivered intra-articularly in conjunction with rehabilitative therapy and an unloading knee brace. The injection of the viscosupplementation is guided such that the entire dose is delivered to the joint and can flow tricompartmentally.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims benefit of U.S. Provisional Patent ApplicationSer. No. 61/784,782, filed Mar. 14, 2013, which is incorporated hereinby reference.

BACKGROUND OF THE INVENTION

1. Field of the Invention

Embodiments of the present invention generally relate to jointrehabilitation. More specifically, embodiments generally relate tomethods of using a combination therapy including a viscosupplementationand physical therapy for joint rehabilitation in a patient.

2. Description of the Related Art

Knee osteoarthritis (OA) is among the most common causes ofmusculoskeletal pain and disability in the United States. Since there isno cure for OA at present, the primary aims of treatment are to reducepain, maintain or improve function and mobility, and prevent or slow theprogression of adverse changes to the joint tissues, while keepingpotential therapeutic toxicities to a minimum. Current treatmentguidelines begin with non-pharmacologic protocols, such as patienteducation, weight loss, and physical therapy.

Non-pharmacologic approaches frequently provide insufficient pain reliefand restoration of function and mobility, and pharmacologic modalitiesbecome necessary. Although simple analgesics such as non-steroidalanti-inflammatory drugs (NSAIDs) provide relief for many OA patientswith mild to moderate pain, alternatives should be considered forpatients who fail to obtain adequate symptomatic relief with thesemeasures. Although NSAIDs and/or cyclooxygenase 2 (COX-2) selectiveinhibitors are frequently effective for the relief of moderate to severeOA pain, these options are not always effective, and may beinappropriate in patients with gastrointestinal or cardiovascular riskfactors. Furthermore, analgesics are designed to prevent the sensationof pain and thus will not prevent or delay further degradation of thejoint.

For patients who do not get adequate pain relief from simple analgesics,like acetaminophen or from exercise and physical therapy,intra-articular injections of hyaluronate provide another treatmentoption to address symptomatic pain and delay the need for a total jointreplacement surgery. It is known that the concentration of nativehyaluronate is deficient in individuals suffering from OA and,therefore, joint injections of exogenous hyaluronate is believed toreplenish these molecules and restore the viscoelastic properties ofsynovial fluid. It is this property that is responsible for lubricatingand cushioning the joints. Independent of the mechanism of action, painrelief can be observed for about six months following a treatment courseof hyaluronate. A treatment course for hyaluronate products on the USmarket can range from single injection product to others that require 3to 5 once a week injections to attain this durability of pain relief.

However, as stated previously, pain relief does not solve the problem.Analgesics mitigate the pain but provide minimal benefit to stemming theprogression of OA in the knee. Hyaluronate or physical therapy ascurrently provided also reduce pain to some extent, but overalldegradation of the joint is not significantly affected. As such, thereis a need in the art for better methods of treatment for OA.

SUMMARY OF THE INVENTION

Embodiments of the present invention generally relate to methods for useof hyaluronate and physical therapy for joint rehabilitation in OApatients. In one embodiment, a method of treatment for a joint caninclude determining a site of injection in a knee of a patient usingflow determination imaging, injecting a volume of a medium to highmolecular weight hyaluronate composition into the selected site ofinjection, wherein the high molecular weight hyaluronate compositionflows tricompartmentally, providing one or more rehabilitation routinesto the patient, wherein the rehabilitation routines increase blood flowand strengthen muscles proximate to the joint and supporting the kneeusing a weight bearing support at least during one of the one or morerehabilitation routines.

In another embodiment, a method for treating osteoarthritis in a patientcan include providing an unloading knee brace for supporting a knee of apatient such that at least a portion of the weight born by the knee issupported by the brace, determining an injection site in the knee of thepatient, the injection site selected to allow for tricompartmental flow,injecting a volume of a hyaluronate composition into the injection sitewith fluoroscopic guidance and providing one or more rehabilitativeexercise sessions to the patient. The hyaluronate composition caninclude a high molecular weight hyaluronate and a diluent, wherein thevolume of the diluent and the high molecular weight hyaluronate isgreater than 2.0 ml, such as at least 2.5 ml. In another embodiment, amethod for treatment of a joint can include determining whethertricompartmental flow exists in an affected knee joint of a patient,affixing a weight bearing support to the affected knee joint of thepatient, wherein the affected knee joint has one or more degenerationsites, if tricompartmental flow exists, determining one or more sites ofinjection in the affected knee joint which allow tricompartmental flowand are proximate to one or more degeneration sites in the affected kneejoint, wherein the sites of injection are determined using flowdetermination imaging, injecting a hyaluronate composition comprisinghyaluronate with a molecular weight of greater than 500 kD, such asgreater than 700 kD, into the one or more sites of injection usingfluoroscopic guidance, the injection delivered from three to five timeswith a separation between injections of seven to ten days and providingone or more physical therapy rehabilitative routines to the patientbefore each injection, the routines designed to strengthen a musclegroup which reduces pressure on at least one of the one or moredegeneration sites.

BRIEF DESCRIPTION OF THE DRAWINGS

So that the manner in which the above recited features of the presentinvention can be understood in detail, a more particular description ofthe invention, briefly summarized above, may be had by reference toembodiments, some of which are illustrated in the appended drawings. Itis to be noted, however, that the appended drawings illustrate onlytypical embodiments of this invention and are therefore not to beconsidered limiting of its scope, for the invention may admit to otherequally effective embodiments.

FIG. 1 depicts a right knee joint showing three compartments;

FIG. 2 is a block diagram of a method for joint rehabilitation accordingto one embodiment;

FIG. 3 is a block diagram of a method for combinatorial therapyincluding hyaluronate and rehabilitative therapy according to oneembodiment; and

FIG. 4 is a block diagram of a method for combinatorial therapyincluding hyaluronate and rehabilitative therapy according to anotherembodiment.

To facilitate understanding, identical reference numerals have beenused, where possible, to designate identical elements that are common tothe figures. It is contemplated that elements disclosed in oneembodiment may be beneficially utilized on other embodiments withoutspecific recitation.

DETAILED DESCRIPTION

Embodiments described herein generally relate to joint rehabilitationusing combinatorial therapy. By combining rehabilitation therapy with atargeted large volume injection of a medium to high molecular weightviscosupplementation, such as hyaluronate, into a space which allows fortricompartmental flow, the viscosupplementation can be delivered to allthree compartments of the joint. The benefits here include decreasedpain both during and after rehabilitation therapy, better proprioceptionduring and after rehabilitation therapy, and increased anti-inflammatoryresponse both in OA damaged compartments of the knee and compartmentswhich may not yet be affected. By decreasing the inflammatory response,reducing pain and increasing stability, the patient is more capable ofperforming physical therapy. Further, reduced pain and increasednon-stressed mobility in the joint increases patient compliance withrehabilitation, thus providing synergistic results. These benefits canbe further enhanced by an unloading or weight bearing knee brace, thussupporting the joint during movement. The invention disclosed herein canbe more clearly understood with reference to the figures described belowwhich illustrate embodiments of the invention.

FIG. 1 is a frontal view of a knee joint 100 depicting the threecompartments. In this depiction, a femur 102, a tibia 104 and a patella106 are shown forming the knee joint 100. The femur 102 has two distinctprotrusions at its lower (distal) end, known as the lateral condyle andthe medial condyle. These protrustions provide two weight bearingsurfaces between the tibia 104 and the femur 102. The space between theweight bearing surface on the outer side of the knee 100 is a firstcompartment 108, which corresponds to the lateral femoro-tibialcompartment. The space between the weight bearing surface on the innerside of the knee 100 is a second compartment 110, which corresponds tothe medial femoro-tibial compartment. A third compartment 112 is in thecenter of the knee, formed between the patella 106 and the space betweenthe lateral and medial condyle of the femur 102, which corresponds withthe patellofemoral compartment.

In a normal knee joint 100, the first compartment 108, the secondcompartment 110 and the third compartment 112 include synovial fluid,including endogenous hyaluronate, articular cartilage and the medial andlateral meniscus that help protect the weight bearing surfaces of thefemur 102 and the tibia 104 during movement. Hyaluronate is aglycosaminoglycan (GAG), and in particular hyaluronate is an unbranchedpolysaccharide made up of alternating glucuronic acid and N-acetylglucosamine units. It is a viscoelastic material that is also found inthe extracellular matrix of cartilage attached to collagen. Inparticular, hyaluronate is an important building component of aggregatedproteoglycans which impart resilient characteristics of articularcartilage.

However, in OA, the articular cartilage of the first compartment 108,the second compartment 110, the third compartment 112 or combinationsthereof degrades, at least in part, by gradual loss of its extracellularmatrix (ECM), which is composed, at least in part, of aggrecan and typeII collagen. Loss of large proteoglycan aggrecan decreases cartilagecompressive stiffness and precedes the damage to collagen fibrillarnetwork, which is responsible for tensile properties of the tissue. Thisprogressive degradation decreases the separation between the weightbearing surfaces and causes pain in the knee joint 100. Hyaluronate canprovide several important functions in synovial fluid. First, it is alubricant that reduces the friction and increases spacing between thefemur and the tibia. Second, it inhibits certain enzymes that break downarticular cartilage in the joints. Third, it acts as ananti-inflammatory agent within the joint. Fourth, it inhibits pain. Bycushioning and lubricating the joints while maintaining the elasticityof the cartilage, hyaluronate helps maintain the spacing between thefemur 102, the tibia 104 and the patella 106. Hyaluronate can thus beused in combination with rehabilitative therapy to treat disorders ofthe joints, such as OA of the knee.

FIG. 2 is a block diagram of a method 200 for joint rehabilitationaccording to one embodiment. The method 200 begins by determining a“site of injection” of a patient using flow determination imaging, as instep 202. The flow determination imaging used in embodiments herein canbe an arthrogram, as described herein. Initially, a contrast medium isinjected into the intra-articular space. A fluoroscope can be used toprovide guidance in injecting the contrast medium. The contrast mediumcomprises a substance which will not be detrimental to the affected kneewhile simultaneously allowing the internal, non-bone components of theknee to be visualized by arthrogram. Examples of contrast mediums usedin one or more embodiments can include iodinated contrast agents suchas, iopamidol or ioxaglate meglumine.

Once the contrast medium is injected, the affected knee joint can thenbe analyzed by arthrogram. The arthrogram can be performed using meansknown in the art, such as an x-ray machine. For example, a C-armfluoroscopic machine can be used to perform the arthrogram afterinjection of the contrast medium. The arthrogram employs a series ofx-rays of the joint with the contrast medium to acquire a threedimensional view of the joint. In one or more embodiments, thearthrogram is taken from anterior (front) to posterior (back) andlaterally, such that a full three dimensional view is shown. Based onthe visualization of the intra-articular compartments, one or more sitesof injection can be determined such that the injection can flowtricompartmentally. Arthrograms used in one or more embodiments hereincan be taken either in a flexed or extended knee position to determinepositions that will allow tricompartmental flow in the flexed position,the extended position or both. Other means of determining a point ofinjection which allows for tricompartmental flow in a knee joint may beused without diverging from embodiments described herein. Though theabove description focuses on the use of arthrograms to determinetricompartmental flow, any known flow determination imaging can be used.Other flow determination imaging techniques or apparatus may be usedwithout diverging from the inventive aspects described here. Forexample, tricompartmental flow may be determined by arthrography or byinjecting a radiolabeled metabolite.

Current practice in OA treatment for intra-articular injection is toinject a viscosupplementation on the lateral side without determinationof a site of injection. This is believed to result in incompleteinjection of the viscosupplementation and subsequent partial injectioninto soft tissue (such as fat pads or ligaments) or misplacement of theentire injection into the soft tissue. Either of these events can createa pseudoseptic response in the patient. Pseudosepsis is a noninfectiousdisorder that mimics sepsis. Symptoms of pseudosepsis can includefever/leukocytosis, hypotension, severe joint inflammation/pain andeffusion (collection of fluid in the surrounding tissue). Therefore, itis important to maintain proper intra-articular injection both forpatient wellbeing and for proper rehabilitation of the affected knee.Proper placement of the intra-articular injection allows completedelivery of the hyaluronate composition to the affected and surroundingcompartments. Complete delivery of the hyaluronate composition providesbetter cushioning for the compartments of the joint, thus allowingincreased mobility and decreased inflammation in the affected knee.

The method 200 further includes injecting a medium to high molecularweight hyaluronate composition into the site of injection. The site ofinjection is selected to allow the medium to high molecular weighthyaluronate composition to flow tricompartmentally, as in step 204.Using the arthrogram analysis described above, a specific injection sitecan be selected. At this point, the hyaluronate composition including ahigh molecular weight hyaluronate is then injected into theintra-articular space. In this instance, medium to high molecular weighthyaluronate means hyaluronate with a molecular weight of greater than orequal to 500 kilo Daltons (kD). In one embodiment, the molecular weightcan be between 500 kD to 10000 kD, such as between 500 kD to 6000 kD. Inanother embodiment, the molecular weight can be from 500 kD to 1700 kD,such as from 600 kD to 1100 kD. In further embodiments, the molecularweight can be greater than 700 kD, such as greater than 800 kD, greaterthan 900 kD or greater than 1000 kD. The hyaluronate can be a nativeform of hyaluronate or a conjugated form of hyaluronate. Further, thehyaluronate compositions used in the embodiments described herein may beentirely a specific weight, a specific weight range (such as from 700 kDto 1000 kD) or a combination of weight ranges. For example, thehyaluronate compositions may include from 0.4% to 0.8% w/v hyaluronate,wherein the hyaluronate includes both from 0.3% to 0.5% w/v of between600 kD to 1100 kD hyaluronate and from 0.1% to 0.5% w/v of a lowmolecular weight hyaluronate (less than 600 kD) dissolved in a 0.9%-1.0%(physiological) saline solution. Examples of hyaluronate compositionswhich can be used in embodiments of the invention include SUPARTZ®available from Bioventus LLC located in Durham, N.C.

Without intending to be bound by theory, it is believed that the mediumto high molecular weight hyaluronate provides a synergistic benefit incombination with physical therapy which both reduces the progression ofOA and increases the pain reduction benefit. First, the medium to highmolecular weight hyaluronate is a longer chain molecule which isbelieved to decrease the rate of molecular degradation and increase theresidence time of the molecule in the knee. The increased residence timeprovides an increased reduction of pain over lower weight compositions.As described previously, hyaluronate is an unbranched polysaccharidemade up of alternating glucuronic acid and N-acetyl glucosamine units.As the hyaluronate breaks down into a smaller chain molecule,viscosupplementation properties decrease and the monomers can eventuallybe removed from the joint by normal metabolism. The longer chainhyaluronate molecule is believed to require more metabolism prior toremoval from the body, due at least in part to steric hindrance frommultiple proteins binding at sites along the unbranched chain. Sincemetabolism is inhibited by the longer chain, the residence time, andthus the physiological benefits, of the hyaluronate is believed to beincreased.

Second, the high molecular weight hyaluronate degrades to a lowermolecular weight hyaluronate, thus increasing the half-life forpharmaceutical-like properties of hyaluronate. Hyaluronate has beenobserved to create an anti-inflammatory response when delivered properlyto the intra-articular space of the knee. One possible route ofpharmacological activity may be through binding to the CD44 receptor.CD44 is involved both in degradation of hyaluronate, cell adhesion,lymphocyte activation/mobilization and hematopoiesis. It is believedthat by introducing a medium to high molecular weight hyaluronate,degradation of the existing/endogenous hyaluronate is slowed by theaforementioned enzymatic mechanism of breaking down a higher molecularweight hyaluronate into a lower molecular weight hyaluronate, thusincreasing the longevity of the pharmacological activity thataccompanies the physical properties of hyaluronate. Further, it isbelieved that the presence of hyaluronate in the tricompartmental spaceleads to the production of endogenous hyaluronate. As such, the benefitsof tricompartmental hyaluronate injection are self perpetuating.

The injection can be delivered as a single injection at a single site ormultiple injections at a single or multiple sites. The injections neednot deliver equal quantities of the hyaluronate composition. Thehyaluronate composition can further include inert components, such as adiluent. The hyaluronate may be reconstituted or diluted in a diluentsuch as a saline solution. The diluent serves to increase the overallvolume of the hyaluronate and act as a vehicle for delivery of thehyaluronate into the intra-articular area of the joint. The overallvolume for the injection can be at least 2.0 ml. In one embodiment, theoverall volume for the injection is between 2.0 and 2.5 ml. In anotherembodiment, the overall volume for the injection is greater than 2.5 mlIt is believed to be important to increase the overall volume of thehyaluronate composition based on the degeneration of the joint, the sizeof the joint and the body dynamics of the person receiving thehyaluronate injections.

The method 200 can further include supporting the joint using a weightbearing support, as in step 206. Due to the nature of theirosteoarthritis, many patients will suffer pain from arthriticcompressive forces and have additional ligamentous instability. Inconjunction with hyaluronate injections and physical therapy, patientswith moderate to severe osteoarthritis may benefit from the use of aweight bearing supports, such as an off the shelf or custom fittedunicompartmental unloading knee brace, to reduce pain and providestability. These braces or other weight bearing supports have theability to decompress or shift compressive knee joint forces from thedegenerative area to healthy compartments in the knee. They can alsoprovide ligamentous stability anterior/posterior and/or medial/laterallythrough structural support and local perception. Additionally, theweight bearing support can allow for increased activity which canprovide pain relief through sensory stimulation. In one embodiment, theunloading knee bracing is designed to put three points of pressure onthe femur. These points of pressure are believed to force the knee tobend away from the painful aspect of the knee. Stated another way, ittransfers or “unloads” stress or pressure from a degenerated portion ofthe knee to a less-degenerated or healthy portion of the knee.

Before or after the patient has received a hyaluronate injection, thepatient can then be fitted for and receive the weight bearing support,such as the unicompartmental unloading knee brace. There are a number ofbraces that allow for unloading of the knee joint on the market. Thejoint support provided by the weight bearing support can be eithercontinuous or periodic, based on the needs of the patient. Continuouscan be defined as use of the weight bearing support at least 90% of theambulatory time for the patient. Ambulatory time is defined as the timewhich the patient is alert. For example, a patient who is using a weightbearing support continuously may affix the weight bearing support uponwaking up and remove the weight bearing support upon going to sleep. Anyamount of time of use of the weight bearing support which is less thancontinuous, as defined above, is periodic. Stated another way, periodicis use of the weight bearing support for less than 90% of the ambulatorytime. For example, a patient who is using a weight bearing supportperiodically may affix the weight bearing support prior to using thejoint and remove the weight bearing support during any non-active time.

Without intending to be bound by theory, it is believed that unloadingthe knee joint during rehabilitative therapy is beneficial to both painreduction and reduced progression of OA. By reducing the compression onthe compartments of the knee, the patient will experience reduced pain,thus allowing the patient to move the joint more freely. Further, thedecreased weight on the compartments of the knee will increase flow ofthe hyaluronate composition tricompartmentally. This both equilibriatesthe hydrostatic pressure in the intra-articular space of the knee andallows for delivery of the hyaluronate composition to both OA affectedareas of the knee and areas not yet showing degeneration.

The method 200 further provides one or more rehabilitation routines tothe patient, as in step 208. The six to eight week physical therapy andrehabilitation program consists of therapeutic exercises and educationdesigned to increase blood flow and strengthen muscles proximate to thejoint. The therapeutic exercises can also improve overall physicalfunction and reduce pain both at the joint and in related areas of thebody.

The physical therapy algorithm is medically necessary, measurable, andfunctionally based towards addressing activities of daily living (ADLs)and comparing prior functional levels to current functional levels. Thealgorithm challenges the patient on multiple physiological levels, suchas strength, cardiovascular, balance/proprioception and coordination.One to five therapy visits can be scheduled prior to the first injectionto allow for baseline functional testing.

FIG. 3 is a block diagram of a method for combinatorial therapyincluding hyaluronate and rehabilitative therapy according to anotherembodiment. The method 300 includes providing an unloading knee bracefor supporting a knee of a patient such that at least a portion of theweight born by the knee is supported by the brace, as in step 302. Inthis embodiment, an unloading knee brace is provided to the patient toincrease intra-articular flow. In one or more forms of OA,tricompartmental flow may be blocked or inhibited by degeneration of theknee at one or more compartments. By unloading the knee,tricompartmental flow can be temporarily reestablished, thus allowingfor further rehabilitation.

Generally speaking, some patients do not have tricompartmental flow dueto physiological anomalies, degeneration from OA progression,inflammation or for other reasons. The lack of tricompartmental flowprevents the injection of the complete volume of the hyaluronate intothe intra-articular space which both reduces the efficacy of thehyaluronate and increases the likelihood of the injection flowing intothe soft tissue. As such, these patients generally do not receive thefull benefit of hyaluronate injection and rehabilitative therapy. Byartificially increasing the tricompartmental flow using an unloadingknee brace, these issues can be partially or completely remedied,allowing a larger patient population to benefit from the methodsdescribed herein.

The method 300 further includes determining an injection site in theknee for the patient. The injection site is selected to allow fortricompartmental flow, as in step 304. As described with reference toFIG. 2, the one or more injection sites can be determined by flowdetermination imaging, such as an arthrogram. The injection sites areinitially determined based on tricompartmental flow. As a secondaryconsideration, sites that are closer to at least one of the degenerationsites are preferable to other sites.

The method 300 further includes injecting a hyaluronate composition intothe injection site, as in step 306. The hyaluronate composition caninclude a high molecular weight hyaluronate and a diluent. The volume ofthe high molecular weight hyaluronate and the diluent can be at least2.0 ml. As described above, greater volumes can be used withconsideration of co-morbidities of the patient or patient-specificphysiological differences. For example, the volume of the hyaluronatecomposition can be increased for a patient with a larger than normalknee joint or for an obese patient.

On the day of injections, the hyaluronate injections should be donefollowing rehabilitative therapy. Rehabilitative therapy can beperformed three times a week. The rehabilitative therapy can actsynergistically with the hyaluronate by increasing the mobility of thehyaluronate composition across the three compartments. Injections can bedone once every five to ten days, such as once every seven to ten days.The injections should be given between three and five times, such as atotal of five injections. In embodiments where three injections ofhyaluronate are used, injections can be given every ten days.

The method 300 further includes providing one or more rehabilitativeexercise sessions prescribed to the patient, as in step 308. Therehabilitative therapy sessions generally begin with medical evaluation,followed by the exercise regimen. Rehabilitation therapy can be giventhree to five times a week over a period of six to eight weeks. In someembodiments, rehabilitation is given over a period of eight weeks atthree times per week.

FIG. 4 is a block diagram of a method for combinatorial therapyincluding hyaluronate and rehabilitative therapy according to anotherembodiment. The method 400 includes determining that tricompartmentalflow exists in an affected knee joint of a patient, as in step 402. Thearthrogram or other flow determination imaging can be performed asdescribed with reference to FIGS. 2 and 3.

A patient who does not have tricompartmental flow in the affected kneejoint, even with assistance, generally receives a less substantialbenefit from this intervention than a patient who does havetricompartmental flow. By determining whether a patient hastricompartmental flow prior to beginning any intervention, the level ofbenefit received can be determined and steps can be taken to increasethe benefit received. For example, in one embodiment the patient can bedetermined to have limited tricompartmental flow. The patient in thisembodiment, may be fitted with a weight bearing support and reevaluatedfor tricompartmental flow after a period of time, such as two weeks.Further, this analysis can determine if there are contraindications toperforming subsequent steps. Contraindications can include other jointissues like meniscal tears, anterior cruciate ligament (ACL) injury,posterior cruciate ligament (PCL) injury or other injuries that affectthe patient's ability to receive the above treatment.

The method 400 can further include affixing a weight bearing support tothe affected knee joint of the patient, wherein the affected knee jointhas one or more degeneration sites, as in step 404. The weight bearingsupport used with embodiments herein can include those described withreference to FIGS. 2 and 3. As described above, the weight bearingsupport can be used to increase tricompartmental flow. However, theweight bearing support provides benefit to both a patient either with orwithout tricompartmental flow.

When a patient has a degenerative disorder, the patient can enter intowhat is colloquially known as a “degenerative cycle”. As people developOA either from injury and hereditary causes, the knee senses the injuryand enzymes are released in to the knee to fight the injury. Theseenzymes, known as hyaluronidases break down hyaluronate and cartilagestarting a downward spiral. As OA progresses there is less and lesshyaluronate within the knee and OA related joint degeneration progressesfaster. As expected, degeneration of the joint causes pain in thepatient. This pain causes the patient to minimize movement and pressureon the joint. The movement, which would normally assist the flow ofvarious healing factors (such as cytokines, leukocytes, endogenousopioids, blood vessel growth factors and the like) into and around thejoint, is no longer present, which both slows down healing and increasesnociception. The slowed healing leads to increased degeneration andincreased pain in the joint as well as atrophy of the surroundingmuscles, thus perpetuating the degenerative cycle. By lifting weightfrom the joint and increasing tricompartmental flow in the joint incombination with other interventions such as hyaluronate, this cycle canbe slowed and/or reversed.

The method 400 can further include determining one or more sites ofinjection in the affected knee which allow tricompartmental flow and areproximate to one or more degeneration sites in the affected knee joint,wherein the sites of injection are determined using flow determinationimaging, as in step 406. By using flow determination imaging, such asthrough an arthrogram, to determine both tricompartmental flow and aproper site of injection, the hyaluronate composition can be injectedinto the joint with a high degree of medical certainty (approaching100%), while injecting the entire volume.

Without intending to be bound by theory, it is believed that the volumeof the hyaluronate delivered is important to the overall success of theintervention. Degeneration in OA is generally marked with loss ofcartilage, decreased production of synovial fluid, ECM degeneration ofthe contacting portions of the bone and aberrant immune response. As thejoint (both bone and space between) degenerates, pain increases and thebones are allowed to make more contact. Injecting a volume into thejoint in a space which allows for tricompartmental flow createsincreased spacing and a consistant hydrostatic pressure across thejoint. A larger volume injected within a range of tolerance creates amore natural separation between the bones and allows for more uniformdelivery of the hyaluronate composition injected into the space. Themore uniform delivery both increases lubrication locally in thecompartment and allows for better receptor binding on type B synovialfibroblasts, which are located in the linings of the knee joints.Binding of hyaluronate to the receptors creates a positive feedback loopand, through one or more signal transduction pathways, the fibroblastscan then generate endogenous hyaluronate. This is believed to bothreduce pain, reverse the catabolic pathways and provide for betteroverall outcomes.

The method 400 further includes injecting a hyaluronate compositioncomprising hyaluronate with a molecular weight of greater than 700 kDinto the one or more sites of injection with fluoroscopic guidance. Theinjection can be delivered from three to five times with a separationbetween injections of seven to ten days, as in step 408. The highmolecular weight hyaluronate can be delivered as a singleintra-articular injection at the site of injection once every seven toten days. The injection can be given three to five times over the courseof a six to eight week rehabilitation session. If fewer injections aregiven, the time between injections should be increased, to increase thebenefit received and allow for the optimum number of physical therapyexercise sessions.

Without intending to be bound by theory, hyaluronate can be consideredboth a device and a pharmaceutical. As with most pharmaceuticals, thedose given is designed to create a therapeutic level of the drug in thecompartment. Factors affecting the therapeutic level of the drug includecompartmentalization and drug metabolism. The treatment regimen ofhyaluronate is designed to be given once a week over a period of fiveweeks. Based on half-life of the drug, most patients will receive directbenefit from the five injections of hyaluronate for a period of fiveweeks. Some patients, however, may require fewer injections to maintainappropriate levels of hyaluronate and/or appropriate volume of fluid inthe joint. These patients may receive as few as three injections. Sincethe goal of the injections is to maintain a specific amount of thecomposition in the tricompartmental space over the six to eight weekcourse of rehabilitation, fewer injections should be extended over alonger period of time with the intent to maintain the therapeutic levelof the hyaluronate during the course of the rehabilitation therapy.

The method 400 further includes providing one or more rehabilitativeroutines to the patient after each injection. The routines arepreferably designed to strengthen at least one muscle which reducespressure on at least one of the one or more degeneration sites, as instep 410. Reducing pressure on the knee joint and strengthening thesurrounding muscles is important to the overall success of the therapy.By increasing muscle growth, not only do you reduce pressure on thejoint but you increase vascularization of the surrounding tissue.

CONCLUSION

Embodiments described herein relate to methods of rehabilitating a kneejoint. As of 2005, OA affects approximately 13.9% of the U.S. populationover the age of 25, and this proportion is steadily increasing. There isno known cure for OA, thus patients rely largely on variousinterventions to both improve outcomes and quality of life. Embodimentsdescribed herein disclose methods of combinatorial therapy whichimproves patient recovery and quality of life over previously knowntechniques or methods. By incorporating an injection of a medium to highmolecular weight hyaluronate composition injected intra-articularly at aposition which has been determined to allow for tricompartmental flowwhile simultaneously providing targeted rehabilitative exercises,patients receive a significantly better outcome than other treatmentswhich are available. The benefits of the above combinatorial therapy canbe further enhanced by the periodic or consistent use of a weightbearing support.

While the foregoing is directed to embodiments of the present invention,other and further embodiments of the invention may be devised withoutdeparting from the basic scope thereof, and the scope thereof isdetermined by the claims that follow.

What is claimed is:
 1. A method for treating osteoarthritis in a patient comprising: providing an unloading knee brace for supporting a knee of a patient such that at least a portion of the weight born by the knee is supported by the brace; determining an injection site in the knee of the patient, the injection site selected to allow for tricompartmental flow; injecting a volume of a hyaluronate composition into the injection site with fluoroscopic guidance, the hyaluronate composition comprising: a high molecular weight hyaluronate; and a diluent, wherein the volume of the diluent and the high molecular weight hyaluronate is at least 2.5 ml; and providing one or more rehabilitative exercise sessions to the patient.
 2. The method of claim 1, wherein the high molecular weight hyaluronate is a non-conjugated hyaluronate.
 3. The method of claim 1, wherein the high molecular weight hyaluronate has a molecular weight between 600 kD to 1100 kD.
 4. The method of claim 3, wherein the hyaluronate composition comprises from 0.3% to 0.5% w/v of high molecular weight hyaluronate.
 5. The method of claim 1, wherein the rehabilitative exercise sessions occur three to five times a week at the clinic (and utilizing a home exercise program) over a period of six to eight weeks.
 6. The method of claim 5, wherein the hyaluronate composition is injected starting on week 1 or week
 2. 7. The method of claim 1, wherein the determination of the injection site comprises an arthrogram, the arthrogram taken at least from anterior to posterior.
 8. The method claim 1, wherein the hyaluronate injection is given once a week for a period of three to five weeks and are given prior to the rehabilitative exercise sessions for the same week.
 9. A method for treatment of a joint comprising: determining whether tricompartmental flow exists in an affected knee joint of a patient; affixing a weight bearing support to the affected knee joint of the patient, wherein the affected knee joint has one or more degeneration sites; if tricompartmental flow exists, determining one or more sites of injection in the affected knee joint which allow tricompartmental flow and are proximate to one or more degeneration sites in the affected knee joint, wherein the sites of injection are determined using flow determination imaging; injecting a hyaluronate composition comprising hyaluronate with a molecular weight of greater than 700 kD into the one or more sites of injection using fluoroscopic guidance, the injection delivered from three to five times with a separation between injections of seven to ten days; and providing one or more physical therapy rehabilitative routines to the patient before each injection, the routines designed to strengthen a muscle group which reduces pressure on at least one of the one or more degeneration sites.
 10. The method of claim 9, wherein the hyaluronate composition has a volume of at least 2.5 ml.
 11. A method for treating osteoarthritis in a patient comprising: providing an unloading knee brace for supporting a knee of a patient such that at least a portion of the weight born by the knee is supported by the brace; determining an injection site in the knee of the patient, the injection site selected to allow for tricompartmental flow; injecting a volume of a hyaluronate composition into the injection site with fluoroscopic guidance, the hyaluronate composition comprising: a high molecular weight hyaluronate; and a diluent, wherein the volume of the hyaluronate composition is at least 2.5 ml; and providing one or more rehabilitative exercise sessions to the patient. 